Delivery means for biologically active agents

ABSTRACT

A sustained release delivery means comprising a biologically active agent and a hydrophilic linear block poly oxyalkylene- polyurethane copolymer.

This application is a continuation-in-part of Ser. No. 855,332, filedNov. 28, 1977, now U.S. Pat. No. 4,202,880, HSC Apr. 11, 1980.

This invention relates to a delivery means for a biologically activeagent, and more particularly it relates to a new means for the sustainedrelease of a biologically active agent in human beings or non-humananimals.

Various sustained release means have been proposed which comprise apolymeric carrier material in combination with a biologically activeagent. For example, pharmaceutical preparations have been proposed inUnited Kingdom Pat. No. 1,135,966 which comprise a polymeric hydrogel(obtained by copolymerising a hydrophilic mono-olefinic monomer with 0.1to 5% of a cross linking agent) which has incorporated within it asoluble biologically active substance. In U.S. Pat. No. 3,857,932 thereare proposed sustained release medicament-containing implantation dosageforms comprising a water-insoluble hydrophilic polymer selected frompolymers of hydroxy lower alkyl (meth)acrylates or hydroxy lower alkoxylower alkyl (meth)acrylates. In German Pat. No. 2,528,068 there areproposed inter alia medicament carrier systems comprising a medicamentand a water-insoluble hydrophilic copolymer comprising (A) 30-90% of ahydrophilic polymer or copolymer obtained from monoolefinic monomer(s)and (B) 10-70% of a hydrophobic polymer having diolefinic terminalgroups.

In U.S. Pat. No. 3,975,350 there are proposed active agent carrier,release, membrane, coating and sensing systems comprising an activeagent in combination with a polyurethane polymer. More particularly,that specification discloses said systems wherein the combination isenhanced by polymers which absorb water. The main thrust of thedisclosure of the specification (see, for example, column 7, lines 33 to40 and lines 64 to 68, and the claims) is towards the use ofcross-linked, and in particular thermoset, polymers. It is alsoindicated that the preferred diisocyanates (for use in preparing thepolyurethane polymers) are aliphatic diisocyanates, and in particularmethylene di(cyclohexyl isocyanate) and adiponitrile carbonate, and thataromatic diisocyanates are vastly less desirable (see column 9, lines50-51 and 63-64).

Although the main thrust of the disclosure and claims of said U.S. Pat.No. 3,975,350 is towards cross-linked polymers, in one Example therein(Example G) there is disclosed a linear copolymer obtained from`Carbowax` 1540, diethylene glycol and `Hylene` W (a light stablediisocyanate having an equivalent weight of 131, produced by Du Pont).However, the polymers used according to the present invention differfrom this polymer in that they are characterised by the presence of ashort chain oxyalkylated diphenol as the dihydroxy component, incontrast to the diethylene glycol used in said Example G.

The said U.S. Pat. No. 3,975,350 neither teaches, nor does it renderobvious to one of ordinary skill in the art, the compositions of thepresent invention and their properties. More particularly, thatspecification does not clearly disclose any block copolymers containingpolyurethane regions and polyoxyalkylene regions, and its main thrust istowards polymers which are not block copolymers as so defined, andtowards crosslinked polymers and therefore away from the linearnon-crosslinked polymers which characterise this invention. Nor is itobvious that the compositions of this invention, which are characterisedby the fact that they involve linear block copolymers, would haveparticularly advantageous physical properties, in particular as regardsthe release of biologically active agents. The compositions of theinvention have the following advantages over the compositions disclosedin said U.S. Pat. No. 3,975,350:

1. They are well characterised block copolymers of high molecular weightprepared by a homogeneous one stage reaction.

2. They have unexpectedly improved mechanical properties when wet.Normally, water would plasticise the hydrophilic polymer, leading to adeterioration in properties (hence the main thrust in said U.S. Pat. No.3,975,350 towards cross-linking, to provide a polymer with adequateproperties when wet). Cross-linking is not needed with the presentinvention as the polymers, even though linear, are designed to haveimproved properties when wet.

3. Because of the lyophilic nature of the polyurethane blocks preparedusing the diphenol derivative, the polymers of this invention have goodsolubility properties in a wider range of solvents.

4. The compatibility of the polymers of this invention with biologicallyactive agents is better over a wider range ofhydrophilicity/lipophilicity.

5. The polymers of this invention have good hydrolytic stability, evenwhen prepared from aromatic diisocyanates, which are preferred toaliphatic diisocyanates in this invention (compare column 9, lines 60 to64 of U.S. Pat. No. 3,975,350).

6. The polymers of this invention are easy to fabricate, and thereforethere is less risk of decomposition of the biologically active agent.

The hydrophilic linear block copolymer which characterises thisinvention has the following advantageous properties:

(1) Because it is linear in structure, the copolymer is soluble incommon organic solvents; this is important for biological applicationsbecause the copolymer can be purified, and solvent casting techniquescan be used for fabrication purposes. Also, the copolymer isthermoplastic and easily moulded and extruded.

(2) It is substantially insoluble and non-erodable in body fluids.

(3) It is compatible with delicate body tissues, and causes no toxicityor related problems.

(4) The degree of hydrophilicity, and therefore of water-swellability,of the copolymer can be pre-determined by its composition. In use, thedelivery means of the invention is permeated by the body fluids, whichresults in a diffusion path being established from the delivery means tothe adjacent body tissue. As a result, there is a sustained release ofthe biologically active agent.

(5) It is a soft elastomer when swollen in body fluids, and therefore itcan conform to body cavities and is nonirritant.

(6) A wide range of biologically active agents, as far as watersolubility is concerned, can be incorporated, in solution or insuspension, in the copolymer.

According to the invention there is provide the sustained releasedelivery means comprising (a) a functionally effective amount of abiologically active agent, (b) a hydrophilic linear blockpolyoxyalkylene-polyurethane copolymer of the type ABABAB . . . ,substantially devoid of cross-linking, wherein A represents ahydrophilic region composed of one or more polyoxyalkylene(s) containingthe repeating unit --(CH₂)₂ O--, --CH₂ CH(CH₃)O--, --(CH₂)₃ O-- and/or--(CH₂)₄ O--, and B represents a hydrophobic region composed of apolyurethane obtainable in known general manner from an aromatic oraliphatic diisocyanate and a short chain oxyalkylated diphenol,optionally together with at least one alkyleneglycol of not more than 6carbon atoms, and (c) optionally containing a biologically acceptablebuffer.

The biologically active agents used according to this invention includemedicaments for the curative or therapeutic treatment of human beings ornon-human animals, as well as agents having desirable pharmacologicalproperties but which do not have actual curative or therapeuticproperties. An example of the latter type of agent is a contraceptiveagent. Thus, included amongst the biologically active agents which aresuitable for administration according to the present invention are:abortifacients, hypnotics, sedatives, tranquillisers, anti-convulsants,muscle relaxants, anti-parkinson agents, analgesics, anti-pyreticagents, anti-inflammatory agents, local anaesthetics, anti-spasmodics,anti-ulcer agents, anti-microbials, anti-malarials, hormonal agents,androgenic steroids, estrogenic and progestational steroids,sympathomimetic agents, cardiovascular agents, diuretics, anti-parasiticagents, anti-tumour agents, hypoglycaemic agents, contraceptive agentsand nutritional agents. The biologically active agents used in thedelivery means of this invention may be sparingly water-soluble,moderately water-soluble or very water-soluble.

The delivery means of the invention is adapted either to be positionedin a body cavity, for example the vagina, or to be implanted in bodytissue, and it can be shaped by standard procedures for the intendeduse.

The copolymers which characterise this invention fall within the classknown as amphipathic materials. A preferred polyoxyalkylene ispolyoxyethylene of molecular weight 600 to 6000. The hydrophobic regionsB are composed of a polyurethane which is obtainable in known generalmanner from a diisocyanate, for example an aromatic diisocyanate, forexample 4,4'-diphenylmethane diisocyanate or toluene diisocyanate (2,4-and/or 2,6-isomers), or an aliphatic diisocyanate, for example1,6-hexamethylene diisocyanate, isophorone diisocyanate or4,4'-dicyclohexylmethane diisocyanate, and a short chain oxyalkylateddiphenol, for example1,1'-isopropylidene-bis-p-phenyleneoxy-di-propanol-2, optionallytogether with at least one alkyleneglycol of not more than 6 carbonatoms, for example ethyleneglycol, diethyleneglycol,1,2-propyleneglycol, 1,3-butyleneglycol or 1,4-butyleneglycol. Aromaticdiisocyanates are preferred over aliphatic diisocyanates.

Preferred copolymers contain 30 to 70% by weight of hydrophilic regionsA and 70 to 30% by weight of hydrophobic regions B. A preferreddiisocyanate is 4,4'-diphenylmethane diisocyanate, because it reacts ata convenient rate without the need for polymerisation catalysts whichmay be leachable and toxic. A preferred dihydroxy compound for use inblock B is 1,1'-isopropylidene-bis-p-phenyleneoxy-di-propanol-2.

According to one embodiment of this invention there is provided asustained release delivery means comprising (a) a functionally effectiveamount of a biologically active agent; (b) a hydrophilic linear blockpolyoxyalkylene-polyurethane copolymer of the type ABABAB . . . ,substantially devoid of cross-linking, wherein A represents ahydrophilic region composed of polyoxyethylene of molecular weight 600to 6000, and B represents a hydrophobic region composed of apolyurethane obtainable in known general manner from an aromaticdiisocyanate and a short chain oxyalkylated diphenol optionally togetherwith at least one alkyleneglycol of not more than 6 carbon atoms, andwherein the copolymer contains 30 to 70% by weight of hydrophilicregions and 70 to 30% by weight of hydrophobic regions; and (c)optionally containing a biologically acceptable buffer.

According to another embodiment of this invention there is provided asustained release delivery means comprising (a) a functionally effectiveamount of a medicament; (b) a hydrophilic linear blockpolyoxyalkylene-polyurethane copolymer of the type ABABAB . . . ,substantially devoid of cross-linking, wherein A represents ahydrophilic region composed of polyoxyethylene of molecular weight 600to 6000, B represents a hydrophobic region composed of a polyurethaneobtainable in known general manner from 4,4'-diphenylmethanediisocyanate and 1,1'-isopropylidene-bis-p-phenyleneoxy-di-propanol-2,and wherein the copolymer contains 30 to 70% by weight of hydrophilicregions and 70 to 30% by weight of hydrophobic regions, and (c) abiologically acceptable buffer.

The buffer which may optionally be present in the delivery means of theinvention may be any biologically acceptable buffer, for example sodiumbicarbonate or a phosphate buffer. The purpose of the buffer is tomaximise the reproducibility of the effect of any particular deliverymeans of the invention in humans or any particular animal, where suchreproducibility is desirable, by standardising the pH of the body fluidsadjacent to the delivery means when it is in position in the host.

The delivery means of this invention can, for example, be obtained byfirst preparing the polymeric component by any standard method, and thenincorporating the biologically active agent and the optionalbiologically acceptable buffer into the copolymer by any standardmethod, for example solvent casting or a compounding procedure. It is tobe understood that the testing of any particular copolymer to ascertainif it is suitable for use according to this invention is a relativelysimple matter which is well within the skill of the art. The amount ofany particular biologically active agent which should be incorporated ina delivery means of this invention is obvious to a skilled person fromhis personal knowledge and/or from the relevant literature, or it iseasily ascertainable by such a person without undue experimentation.Equally, the composition and amount of any buffer which may be presentin a delivery means of this invention are obvious to or easilyascertainable by said skilled person.

One particularly useful embodiment of this invention consists of anintravaginal device comprising an abortifacient compound.

A suitable abortifacient compound is, for example, an abortifacientprostaglandin derivative, for example fluprostenol sodium [racemic (9S,11R,15R)-9,11,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid sodium salt]. A particularly preferredembodiment of this invention consists of an intravaginal devicecomprising a fluprostenol sodium, a biologically acceptable buffer, forexample a phosphate buffer, and a hydrophilic copolymer obtained asdescribed above and containing 60% by weight of polyoxyethylene ofmolecular weight 4000, and 40% by weight of hydrophobic polyurethaneblocks obtained from approximately equal parts by weight of4,4'-diphenylmethane diisocyanate and1,1'-isopropylidene-bis-p-phenyleneoxy-di-propanol-2.

The rate of release in vivo of the abortifacient drug from saidintravaginal device of this invention is determined by the compositionof the copolymer, the size, shape and thickness of the device, thenature and amount of the abortifacient compound, and the nature andamount of any buffer, in the device. Said intravaginal device can be inthe form of a disc, ring, annulus or slab, or any other shape which canbe retained in the vagina.

The invention is illustrated by the following Examples:

EXAMPLE 1

(a) Preparation of copolymer--medicament mixture

Solutions of fluprostenol sodium (5 mg.) in water (0.5 ml.) and of C¹⁴labelled fluprostenol sodium (5 μl. having a concentration of 1 mg./ml.,specific activity 133 μCi/mg.) in water were added to a solution of theelastomer described below (10 g.) in tetrahydrofuran (40 g.). Thesolution was cast as a film in conventional manner. The resulting filmwas air-dried at room temperature for 24 hours and finally dried at 70°C. in vacuo for 8 hours. The resulting polymer-medicament mixture wascompression moulded at 110° C. to give a slab of 0.1 cm. thickness.

The desorption of the medicament and the radioactivity from 2 g. of thesaid slab into water at 37° C., using a stirring rate of 100 r.p.m., wasshown to behave approximately according to the equation: ##EQU1## whereM_(t) is the amount of medicament released by time t, is the totalamount of medicament in the slab,

t is the time,

l is the thickness of the slab, and

D is the diffusion coefficient.

The graph of M_(t) /M.sub.∞ against ^(t).spsp.1/2 /₁ is a straight line,giving a value for D of ca. 5×10⁻⁴ cm² hours⁻¹.

In sink conditions (i.e. where the concentration of the medicament inthe medium into which it is being released in very small) in vitro thesaid slab (0.1 cm. thickness) releases ca. 85% of the total medicamentin 4 hours, whereas with a corresponding slab of 0.17 cm. thickness thisamount of release is achieved in ca. 8 hours.

(b) Preparation of copolymer

The copolymer used in preparing the abovementioned copolymer--medicamentmixture was obtained as follows:

A mixture of polyethyleneglycol (600 g.; molecular weight ca. 4000) andpowdered magnesium silicate (18 g.) was heated at 110° C. in vacuo fortwo hours. The hot mixture was filtered to give a polyol which was dryand free from alkaline residues.

4,4'-Diphenylmethane diisocyanate (91.6 g.) was melted and heated at 80°C., and to it was added a mixture of diethylene glycol (3.3 g.),1,2-propylene glycol (2.3 g.) and 1,3-butylene glycol (2.8 g.). Theresulting mixture was stirred at 80° C. for 2 hours. There was thusobtained a clear viscous diisocyanate derivative (having an isocyanatevalue of 23% by weight), which was used as described below.

The abovementioned polyol (80 g.) and dry1,1'-isopropylidene-bis-p-phenyleneoxy-di-proponal-2 (34 g.) were mixedat 80° C. to give a clear solution. To this was added the abovementioneddiisocyanate derivative (46 g.). The mixture was maintained at 70°-80°C. for 18 hours. The mixture was then cooled to room temperature, andpost cured for 1 week at room temperature, to give a soft, flexibleelastomer. This was purified by dissolution in a mixture of acetone(1500 ml.) and water (500 ml.). To this solution was added a solution ofsodium carbonate (5 g.) in water (50 ml.). The resulting mixture wasstirred at room temperature for 2 hours. The elastomer was precipitatedby adding the polymer solution to vigorously stirred water (ca. 5 l.).The elastomer was separated by filtration, washed with water untilneutral, and dried in vacuo at 80° C. for 24 hours. There was thusobtained a soft, flexible copolymer (elastomer) comprising hydrophilicpolyethyleneglycol regions and hydrophobic polyurethane regions.

EXAMPLE 2

(a) Preparation of an intravaginal device

An aqueous solution of fluprostenol sodium (0.1 ml. having aconcentration of 10 mg./ml.) and an aqueous solution of C¹⁴ labelledfluprostenol sodium (5 μl. having a concentration of 1 mg./ml., specificactivity 133 μCi/mg.) were added to a solution of the dried, purecopolymer prepared as described in Example 1(b) (2 g.) intetrahydrofuran (8 g.). The mixture was homogenised by vigorous shaking.A film was cast from the mixture, allowed to dry in the air at roomtemperature for 24 hours, and finally at 70° C. in vacuo for 8 hours.The resulting copolymer-medicament film (0.02 g.), which contained 10μg. of the medicament, was compression moulded at 110° C. to give a slab(dimensions: ca. 8 mm.×7 mm.×0.2 mm.). This was wrapped round a siliconetube (2.5 mm. outside diameter×10 mm.) to give an intravaginal device inthe form of a medicament-containing annulus supported on a flexiblecore. When these devices were tested in rats (see below) they releasedthe medicament continuously over 24 hours. The amount of medicamentdesorbed from the device was measured by comparing the residualradioactivity with the original radioactivity.

(b) Determination of in vivo release

Rats (Alderley Park strain, weight 250 g.), which were shown by means ofa vaginal smear to be in the first day of dioestrus, were divided into 6groups of two. The animals were treated with an intravaginal device madeas described in Example 2(a).

The devices were removed from individual groups at discrete timeintervals, and the residual radioactivity in the devices was measured.Comparison of this with initial levels of radioactivity showed that themedicament was desorbed from the devices in the following manner:

    ______________________________________                                        Time (hours)       % Drug desorbed                                            ______________________________________                                        2                  15-18                                                      4                  22-35                                                      6                  40-45                                                      8                  40-46                                                      16                 55-62                                                      24                 68-72                                                      ______________________________________                                    

These results show that the drug was desorbed continuously from thedevices over 24 hours when the devices were inserted into the vaginas ofrats.

(c) Testing of intravaginal device in rats

Rats (Alderley Park strain, weight 250 g.), which had been mated andwhose pregnancy had been confirmed by a positive sperm test on a vaginalsmear, were divided into four groups on day 6 after mating. The animals(2) in the first group were untreated controls whose pregnancies wereallowed to proceed normally. The animals (6) in the second group weretreated with an intravaginal device made as described in Example 2(a),but containing no medicament. The animals (6) in the third groupreceived in a single, acute, intravaginal dose of fluprostenol sodium(10 μg.) in water (0.1 ml.). The animals (8) in the fourth group weretreated for 24 hours with an intravaginal device made as described inExample 2(a), after which time the devices were removed. On day 15 aftermating all of the animals were sacrificed, and the number and health ofthe implants were assessed. The results are summarised in Table 1.

                  TABLE 1                                                         ______________________________________                                                                   CON-                                                                          DITION   ABOR-                                               RAT  IMPLANT     OF IM-   TION                                      GROUPS      No.    L*     R*     PLANTS RATE                                  ______________________________________                                        UNTREATED   1      3      7        healthy                                                                              0/2                                 CONTROL     2      1      7        healthy                                                3      4      8        healthy                                    CONTROL-    4      4      5        healthy                                    BLANK       5      4      6        healthy                                                                              0/6                                 DEVICE      6      6      5        healthy                                                7      9      7        healthy                                                8      4      8        healthy                                                9      6      4                                                   SINGLE      10     6      5        mainly                                     ACUTE       11     4      4        healthy -DOSE OF                                                                     1/6                                 MEDICAMENT  12     6      7                                                   (10 μg.  13     7      2                                                   PER RAT)    14     0      0                                                               15     0      0                                                   MEDICAMENT  16     0      0                                                   INTRAVAGINAL                                                                              17     0      0                                                   DEVICE      18     0      0                                                   (10 μg. of                             8/8                                 medicament  19     0      0                                                   available   20     0      0                                                   in each rat)                                                                              21     0      0                                                               22     0      0                                                   ______________________________________                                         *L stands for the left horn of the                                            R stands for the right horn of the uterus                                

The two groups of control animals had healthy implants, showing that theexperimental procedure had had no effect on the pregnancies. Theabortion rate of the rats which received a single acute dose on day 6was much lower (abortion rate 1/6) than that of rats which were treatedfor 24 hours by means of the intravaginal device (abortion rate 8/8).These results indicate that sustained administration of fluprostenolsodium by means of an intravaginal device of this invention gives asuperior effect to that given by a single acute vaginal dose of the samemedicament.

EXAMPLE 3

(a) Preparation of an intravaginal device

Using the procedure described in Example 1(a), there was prepared asolution containing the elastomer described in Example 1(b) (8 g.),fluprostenol sodium (1 mg. in 0.1 ml. of water), and C¹⁴ labelledfluprostenol sodium (20 μl. of an aqueous solution having aconcentration of 1 mg./ml., specific activity of 133 μCi/mg.) andtetrahydrofuran (34 g.). After drying, there was obtained apolymer-medicament mixture containing 10 μg. of fluprostenol sodium per0.08 g. of polymer.

Individual cylinders, each ca. 3 mm. diameter×10 mm., were made by thecompression moulding (at 110° C.) of 0.08 g of the polymer-medicamentmixture described immediately above. When tested in vivo in rats (seebelow), these cylinders released 2.2-2.5 μg. of the medicament during 24hours.

(b) Determination of in vivo release

Rats (Alderley Park strain, weight 250 g.), which were shown by means ofa vaginal smear to be in dioestrus, were divided in 5 groups of two. Theanimals were treated with an intravaginal device made as described inExample 3(a).

The devices were removed from individual groups at discrete timeintervals, and the residual radioactivity in the devices was measured.Comparison of this with initial levels of radioactivity showed that themedicament was desorbed from the devices in the following manner:

    ______________________________________                                        Time (hours)       % Drug desorbed                                            ______________________________________                                        2                  2-4                                                        6                  2-6                                                        12                 8-10                                                       18                 15-18                                                      24                 21-26                                                      ______________________________________                                    

(c) Testing of intravaginal device in rats

Rats (Alderley Park Strain, weight 250 g.), which had been mated andwhose pregnancy had been confirmed by a positive sperm test on vaginalsmear, were divided into three groups on day 6 after mating. The animals(4) in the first group were controls treated with a blank intravaginaldevice; i.e. a device made as described in Example 3(a), but containingno medicament. The animals (6) in the second group received a single,acute, intravaginal dose of fluprostenol sodium (10 μg.) in apolycarboxylate gel (`Carbopol`; 0.1 g.). The animals (7) in the thirdgroup were each treated with an intravaginal device made as described inExample 3(a). After 24 hours these devices were removed, and acomparison of the original and residual radioactivity indicated thateach rat had received 1.7-2.5 μg. of the medicament over the 24 hours.On day 15 after mating, all of the animals were sacrificed, and thenumber and health of the implants were assessed. The results aresummarised in Table 2. These show that, whereas the incidence ofabortion using a single acute vaginal dose of 10 μg. of fluprostenolsodium is 33%, a superior response (57%) is achieved using 1.7-2.5 μg.of the same medicament when administered over 24 hours by means of anintravaginal device of this invention.

                  TABLE 2                                                         ______________________________________                                                    Amount Of                   A-                                                Medicament          Condition                                                                             bor-                                         Rat  Administered                                                                             Implants Of      tion                                  Group    No.    (μg.)       R    Implants                                                                              Rate                              ______________________________________                                        Control- 1      0          7   7    Healthy                                   Blank    2      0          3   9    Healthy 0/4                               Device   3      0          3   7    Healthy                                            4      0          7   5    Healthy                                   Single   5      10         0   0                                              Acute    6      10         0   0                                              Dose of  7      10         5   4    All                                       Medicament                                                                             8      10         7   4    unhealthy                                                                             2/6                               (10 μg.                                                                             9      10         4   5                                              per rat) 10     10         5   8                                              Medicament-                                                                            11     1.7        4   7    Healthy                                   Intravaginal                                                                           12     2.5        0   0                                              Device   13     2.3        0   0                                              (maximum 14     2.3        0   0                                              of 10 μg. of                                                                        15     not        0   0            4/7                               medicament      known                                                         per device                                                                             16     2.4        5   8    Healthy                                   available to                                                                  each rat)                                                                              17     1.7        7   6    Healthy                                   ______________________________________                                    

EXAMPLE 4

(a) Preparation of intravaginal devices

Using the procedure described in Example 1(a) the following solutionswere prepared using the elastomer described in Example 1(b):

(i) Elastomer (2 g.), fluprostenol sodium (1.2 mg. in 0.12 ml. ofwater), C¹⁴ labelled fluprostenol sodium (5 μl. of an aqueous solutionhaving a concentration of 1 mg./ml., specific activity 133 μCi./mg.),sodium bicarbonate (1.2 mg. in 60 μl. of water) and tetrahydrofuran (8g.).

After drying, there was obtained a copolymer-medicament mixturecontaining 12 μg. of fluprostenol sodium per 0.02 g. of copolymer.

The copolymer-medicament mixture (0.02 g.) was compression moulded at110° C. to give a slab (dimensions: ca 10 mm.×15 mm.×0.10 mm.). This waswrapped round a silicone tube (4 mm. outside diameter×15 mm.) to give anintravaginal device in the form of an annulus (dimensions: ca. 10 mm.long×4 mm. outside diameter, and having a wall thickness of 0.1 mm.)supported on a flexible core. The device contained 12 μg. of medicament.

(ii) Using the copolymer-medicament mixture (0.01 g.) described in (i)above a slab was compression moulded having dimensions: ca. 5 mm.×15mm.×0.1 mm. This was wrapped round a silicone tube (4 mm. outsidediameter×15 mm. long) to give an intravaginal device in the form of anannulus (dimensions: ca. 5 mm. long×4 mm. outside diameter, and having awall thickness of 0.1 mm.) supported on a flexible core. The devicecontained 6μg. of medicament.

(iii) Using the copolymer-medicament mixture (0.005 g.) described in (i)above a slab was compression moulded having dimensions: ca. 5 mm.×8mm.×0.1 mm. This was wrapped round a silicone tube (2.5 mm. outsidediameter×15 mm. long) to give an intravaginal device in the form of anannulus (dimensions: ca. 5 mm. long×2.5 mm. outside diameter, and havinga wall thickness of 0.1 mm.) supported on a flexible core. The devicecontained 3 μg. of medicament.

(iv) Elastomer (4 g.), fluprostenol sodium (1.2 mg. in 0.12 ml. ofwater), C¹⁴ labelled fluprostenol (5 μl. of an aqueous solution having aconcentration of 1 μg./ml., specific activity 133 μCi/mg.), sodiumbicarbonate (1.2 mg. in 60 μl. of water) and tetrahydrofuran (16 g.)were mixed to give a solution. After drying, there was obtained acopolymer-medicament mixture containing 12 μg. of fluprostenol sodiumper 0.04 g. of copolymer. The copolymer-medicament mixture (0.04 g.) wascompression moulded at 110° C. to give a slab (dimensions: ca. 10 mm.×15mm.×0.2 mm.). This was wrapped round a silicone tube (4 mm. outsidediameter×15 mm.) to give an intravaginal device in the form of anannulus (dimensions: ca. 10 mm. long×4 mm. outside diameter, and havinga wall thickness of 0.2 mm.) supported on a flexible core. The devicecontained 12 μg. of medicament.

(v) Using the copolymer-medicament mixture (0.02 g.) described in (iv)above a slab was compression moulded having dimensions: ca 5 mm.×15mm.×0.2 mm. This was wrapped round a silicone tube (4 mm. outsidediameter×15 mm.) to give an intravaginal device in the form of anannulus (dimensions: ca. 5 mm. long×4 mm. outside diameter, and having awall thickness of 0.2 mm.) supported on a flexible core. The devicecontained 6 μg. of medicament.

(vi) Using the copolymer-medicament mixture (0.01 g.) described in (iv)above a slab was compression moulded having dimensions: ca 5 mm.×8mm.×0.2 mm. This was wrapped round a silicone tube (2.5 mm. outsidediameter×15 mm. long) to give an intravaginal device in the form of anannulus (dimensions: ca. 5 mm. long×2.5 mm. outside diameter, and havinga wall thickness of 0.2 mm.) supported on a flexible core. The devicecontained 3 μg. of medicament.

(vii) Using the copolymer-medicament mixture (0.004 g.) described in(iv) above a slab was compression moulded having dimensions: ca 2 mm.×8mm.×0.2 mm. This was wrapped round a silicone tube (2.5 mm. outsidediameter×15 mm.) to give an intravaginal device in the form of anannulus (dimensions: ca 2 mm.×2.5 mm. outside diameter, and having awall thickness of 0.2 mm.) supported on a flexible core. The devicecontained 1.2 μg. of medicament.

(b) Determination of in vivo release

In a series of experiments, rats (Alderley Park strain, weight 200 g.),which were shown by vaginal smear to be in the first day of dioestrus,were divided into groups of two. The animals were treated with thedevices described in Example 4(a). The devices were removed fromindividual groups at discrete time intervals, and the residualradioactivity in the devices was measured. Comparison of this withinitial levels of radioactivity showed that the medicament was desorbedfrom the devices in the following manner:

    ______________________________________                                        For devices (i), (ii) and (iii)                                               Time (hours)       % Drug desorbed                                            ______________________________________                                        2                  25-40                                                      5                  40-60                                                      8                  72-92                                                      ______________________________________                                    

The devices were removed at 8hr.

    ______________________________________                                        For devices (iv), (v), (vi) and (vii)                                         Time (hours)       % Drug descorbed                                           ______________________________________                                        4                  21-36                                                      8                  36-55                                                      16                 65-83                                                      24                 67-92                                                      ______________________________________                                    

The devices were removed at 24hr.

These results show that for devices (i), (ii) and (iii) the medicamentwas desorbed continuously from the devices over 8 hr. when these wereinserted into the vaginas of rats. For devices (iv), (v), (vi) and (vii)the medicament was desorbed continuously from the devices over 24 hrs.when these were inserted into the vaginas of rats.

(c) Testing of intravaginal devices in rats

Rats (Alderley Park strain, weight 250 g.), which had been mated andwhose pregnancy had been confirmed by a positive sperm test on a vaginalsmear, were divided into groups of 6 and on day 6 after mating weretreated in the following way:

Group 1. Untreated; pregnancy allowed to proceed normally.

Group 2. Treated with 0.1 ml. of polycarboxylate gel (`Carbopol`)containing no medicament.

Group 3. Treated with intravaginal devices prepared as described inExample 4(a) but containing no medicament.

Group 4. Treated with 0.1 ml. of polycarboxylate gel (`Carbopol`)containing medicament.

Group 5. Treated with device (i), (ii) or (iii). Drug was released over8 hr., at which time the devices were removed.

Group 6. Treated with devices (iv), (v), (vi) or (vii). Drug wasreleased over 24 hr., at which time the devices were removed.

For animals in Groups 5 and 6 the amount of medicament administered wasmeasured by comparing the residual radioactivity with the initialvalues. On day 15 after mating, all the animals were sacrificed, and thenumber and health of the implants were assessed. The results aresummarised in table 3.

                                      TABLE 3                                     __________________________________________________________________________    Rats treated on day 6 of pregnancy. Acute dosing vs. sustained release.                        Average                                                                       amount Time of                                                                drug admin-                                                                          Administration                                                                        No. of                                                    Group                                                                              istered (μg.)                                                                     (hours) rats                                                                              Abortion Rate %                           __________________________________________________________________________      Control-untreated animals                                                                    0      --      6   0                                           Control-blank gel (no drug)                                                                  0      --      6   0                                           Control-blank device (no drug)                                                               0      --      6   0                                           10μg. drug/0.1 ml. gel                                                                    10     acute   8   25                                          5μg. drug/0.1 ml. gel                                                                     5      "       8   38                                          2.5 μg. drug/0.1 ml. gel                                                                  2.5    "       8   0                                           1μg. drug/0.1 ml. gel                                                                     1      "       8   12                                          12μg. drug/0.02 g. copolymer                                                              10.4   8       6   50                                          6μg. drug/0.01 g. copolymer                                                               4.8    8       5   20                                          3μg. drug/0.005 g. copolymer                                                              2.6    8       6   33                                          12μg. drug/0.04 g. copolymer                                                              9.8    24      8   100                                         6μg. drug/0.02 g. copolymer                                                               5.0    24      10  90                                          3μg. drug/0.01 g. copolymer                                                               2.7    24      12  83                                          1.2μg. drug/0.004 g. copolymer                                                            1.0    24      6   0                                         __________________________________________________________________________

The results show that the incidence of abortion in the pregnant rats wasgreater when they were treated with the sustained release devices, andthat at comparable dose levels the response was increased as theduration of administration was extended.

EXAMPLE 5

(a) Preparation of copolymers

Polyethyleneglycol having a molecular weight of 4000 was purified asdescribed in Example 1. The purified, dry product had a hydroxyl valueof 27.6 mg. KOHg.⁻¹. 1,1'-Isopropylidene-bis-p-phenyleneoxy-di-propanol-2 was purified using a procedure similar to that used forpolyethyleneglycol. 4,4'-Diephenylmethane diisocyanate was distilledbefore use (b.p. 160-170° L C./0.1 mm.Hg.).

Using these purified materials the following elastomers were prepared:

A. Polyethyleneglycol (51 g.) and the abovementioned bisphenolderivative (28 g.) were mixed at 80° L C., and the diisocyanate (23 g.)was added. The mixture was thoroughly mixed by stirring and then reactedat 80° C. under dry nitrogen for 36 hrs. The copolymer was cooled toroom temperature and allowed to post-cure for 3 days to give anelastomeric product. The elastomer contained 50% by weight ofhydrophilic block and 50% by weight of hydrophobic block.

B. Polyethyleneglycol (40 g.) and the abovementioned bisphenolderivative (14.1 g.) were reacted with the diisocyanate (12.5 g.) at 80°C. in the manner described above. The resulting elastomer contained 60%by weight of hydrophilic block and 40% by weight of hydrophobic block.

C. Polyethyleneglycol (60 g.) and the abovementioned bisphenolderivative (15 g.) were reacted with the diisocyanate (15 g.) at 80° C.in the manner described above. The resulting elastomer contained 67% byweight of hydrophilic block and 33% by weight of hydrophobic block.

(b) Purification of Elastomers

Elastomers A, B and C were purified as follows:

The elastomer (50 g.) was dissolved in a mixture of absolute ethanol(400 g.) and distilled water (100 g.) at 70° C. Sodium bicarbonate (0.1g. in 2 ml. water) was added and the mixture was stirred at 70° C. for 2hr. The solution was added to distilled water (5 l.), causing thecopolymer to precipitate. The mixture was filtered and the solid residuewashed with distilled water (2 l.). The solid was then stirred indistilled water (3 l.) for 24 hrs., filtered, and dried in vacuo at 80°C.

(c) Preparation of copolymer-medicament mixtures

The following procedure was carried out using each of the copolymers A,B and C:

Solutions of fluprostenol sodium (3 mg. ) in water (0.3 ml.), C¹⁴labelled fluprostenol sodium (80 μl. having a concentration of 0.02mg./ml., specific activity 133 μCi/mg.) in water, and sodium bicarbonate(60 μl. of a solution of 50 mg./ml.) in water, were added to a solutionof the copolymer (3 g.) in tetrahydrofuran (30 ml.). The mixture wascast as film and air dried at room temperature for 24 hr. and finally at70° C. in vacuo for 8 hr. The resulting copolymer-medicament mixture wascompression moulded at 110° C. to give slabs 0.16 cm. thick.

(d) In vitro release of medicament

The desorption of the medicament and radioactivity from 0.5 g. of thesaid slabs was determined in the following way:

The copolymer-medicament slab (0.5 g.) was suspended from a stirrer into500 ml. of phosphate solution buffered to pH 7 (prepared from 3.7 g. ofpotassium dihydrogen phosphate and 5.78 g. of disodium hydrogenorthophosphate dihydrate in 1000 ml. water) maintained at 37° C. Using astirring rate of 100 r.p.m. the desorption of radioactivity was shown tobe approximately proportional to (time)^(1/2). Equilibrium swelling ofthe copolymers at 37° C. in water was:

Copolymer A ca. 100%

Copolymer B ca. 150%

Copolymer C ca. 210%

EXAMPLE 6

(a) Preparation of intravaginal devices.

The following copolymer-medicament mixtures were prepared using theelastomer described in Example 5 (copolymer A):

(i) Elastomer (3 g.), fluprostenol sodium (1.2 mg. in 0.12 ml of water),C¹⁴ labelled fluprostenol sodium (15 μl. of an aqueous solution having aconcentration of 1 mg./ml., specific activity 133 μCi/mg.), sodiumbicarbonate (1.2 mg. in 60 μl. of water) and tetrahydrofuran (13 g.).After drying, there was obtained a copolymer-medicament mixturecontaining 12 μg. of fluprostenol sodium per 0.03 g. of copolymer.

The copolymer-medicament mixture (0.3 g.) was compression moulded at110° C. to give a slab (dimensions: ca. 7 mm.×15 mm.×0.2 mm.). This waswrapped round a silicone tube (4 mm. outside diameter×15 mm.) to give anintravaginal device in the form of an annulus (dimensions: ca. 7 mm×4mm. outside diameter, and having a wall thickness of 0.2 mm.) supportedon a flexible core. The device contained 12 μg. of medicament.

(ii) Using the copolymer-medicament mixture (0.015 g.) described in (i)above a slab was compression moulded having the dimensions ca. 4 mm.×15mm.×0.2 mm. This was wrapped round a silicone tube (4 mm. outsidediameter×15 mm.) to give an intravaginal device in the form of anannulus (dimensions: ca. 4 mm.×4 mm. outside diameter, and having a wallthickness of 0.2 mm.) supported on a flexible core. The device contained6 μg. of medicament.

(iii) Elastomer (1.5 g.), fluprostenol sodium (1.2 mg. in 0.12 ml. ofwater), C¹⁴ labelled fluprostenol sodium (2 μl. of an aqueous solutionhaving a concentration of 1 mg./ml., specific activity 133 μCi/mg.),sodium bicarbonate (1.2 mg. in 60 μl. of water) and tetrahydrofuran (5g.) were mixed to give a solution. After drying, a copolymer-medicamentmixture was obtained which contained 6 μg. of fluprostenol sodium per0.0075 g. of copolymer. The copolymer-medicament mixture (0.075 g.) wascompression moulded at 110° C. to give a slab (dimensions: ca 7 mm.×8mm.×0.1 mm.). This was wrapped round a silicone tube (2.5 mm. outsidediameter×15 mm. long) to give an intravaginal device in the form of anannulus (dimensions: ca. 7 mm.×2.5 mm. outside diameter, and having awall thickness of 0.1 mm.) supported on a flexible core. In non-pregnantrats, the intravaginal devices (i) and (ii) released 70-90% of themedicament over 24 hr., whereas the intravaginal device (iii) released70-90% in 8 hr.

(b) Testing of intravaginal devices in rats.

Rats (Alderley Park Strain, weight 250 g.), which had been mated andwhose pregnancy had been confirmed by a positive sperm test on vaginalsmear, were divided into groups and on day 9 after mating they weretreated in the following way:

Group 1. Untreated; pregnancy allowed to proceed normally.

Group 2. Treated with 10 μg. of fluprostenol sodium in 0.05 ml.polycarboxylate (`Carbopol`) gel.

Group 3. Treated with a device containing 12 μg. of medicament which isreleased over 24 hr.

Group 4. Treated with 5 μg. of fluprostenol sodium in 0.1 mg. ofpolycarboxylate (`Carbopol`) gel.

Group 5. Treated with a device containing 6 μg. of medicament which isreleased continuously over 24 hr.

Group 6. Treated with a device containing 6 μg. of medicament whichreleased 70-90% of medicament in 8 hr.

The devices in Groups 5 to 6 were removed after 24 hrs. and the residualradioactivity measured. Comparing this with initial values enabled theamount of drug administered to be calculated. On day 20 after mating,all the animals were sacrificed and the number and health of theimplants assessed.

                  TABLE 4                                                         ______________________________________                                        Rats treated on day 9 of pregnancy.                                           Acute dosing vs. sustained release.                                                            Average  Time                                                                 drug     for          Abor-                                                   admin-   drug    No.  tion                                                    istered  release of   Rate                                   Group            (μg.) (hr.)   rats %                                      ______________________________________                                        1. Control-untreated animals                                                                   0                3    0                                      2. 10μg. drug/0.05 ml. gel                                                                  10       acute   6    67                                     3. 12μg. drug/0.03 g. polymer                                                               10.2     24      6    100                                    (device i)                                                                    4. 5 μg. drug/0.1 ml. gel                                                                   5.0      acute   5    40                                     5. 6μg. drug/0.015 g. polymer                                                               5.0      24      5    100                                    (device ii)                                                                   6. 6μg. drug/0.0075 g. polymer                                                              5.1      8       3    67                                     (device iii)                                                                  ______________________________________                                    

These results show that an extended duration of administration of themedicament results in a higher abortion rate.

EXAMPLE 7

(a) Preparation of Intravaginal Device.

The following copolymer-medicament mixtures were prepared using theelastomer described in Example 5 (copolymer A):

Elastomer (5 g.), fluprostenol sodium (12 mg. in 1.2 ml. of water), C¹⁴labelled fluprostenol (1 μl. of an aqueous solution having aconcentration of 1 mg./ml., specific activity 133 μCi/mg.), sodiumbicarbonate (12 mg. in 600 ml. of water) and tetrahydrofuran (50 g.).After drying there was obtained a copolymer-medicament mixturecontaining 300 μg. of fluprostenol sodium per 0.125 g. of copolymer. Thecopolymer-medicament mixture (0.125 g.) was compression moulded to givea slab (dimensions: ca. 15 mm×7 mm.×1 mm.). This was wrapped round asilicone tube (4 mm. outside diameter×60 mm. long) to give anintravaginal device in the form of an annulus (dimensions: ca. 7 mm.×6mm. outside diameter, and having a wall thickness of 1 mm.) supported ona flexible core. The device contained 300 μg. of medicament.

(b) Determination of in vivo release

Beagle bitches (weight ˜12-15 kg.) were treated with the intravaginaldevices described in Example 6(a). The devices were removed fromindividual bitches at discrete time intervals, and the residualradioactivity measured. Comparison of this with initial levels ofradioactivity showed that the medicament was desorbed from the devicesin the following manner:

    ______________________________________                                        Time (hr)          % Drug desorbed                                            ______________________________________                                        5                  30                                                         16                 63                                                         24                 80                                                         ______________________________________                                    

These results show that the drug was desorbed continuously from thedevices over 24 hr. when the devices were inserted into the vaginas ofbitches.

(c) Testing of intravaginal device in pregnant bitches.

Beagle bitches (weight 12-19 kg), which had been mated and whosepregnancy had been confirmed by palpation, were divided into 3 groups onday 25 after mating.

Group 1. These animals were treated on both day 25 and day 26 ofpregnancy with annuli devices which had a wall thickness of 1 mm. andwhich released ca. 20-25 μg./kg. of fluprostenol sodium over 24 hr.

Group 2. These animals were treated on day 25 with annuli devices whichhad a wall thickness of 1 mm. and which released ca. 20-25 μg./kg. offluprostenol sodium over 24 hr.

Group 3. These animals were treated on both day 25 and day 26 ofpregnancy with annuli devices which had a wall thickness of 1 mm. andwhich released ca. 10 μg./kg. of fluprostenol sodium over 24 hr.

Blood samples for progesterone assay were taken from all animals in thethree groups before, during and after treatment. The animals werepalpated 1 week and 2 weeks after treatment to assess regression of theimplants. The results are summarised in Table 5.

                  TABLE 5                                                         ______________________________________                                        Treatment of Pregnant Bitches with                                            sustained release intravaginal devices.                                                  Drug                                                                          Admin-  Proges-                                                               istered terone    Im-     Abor-                                               (μg./kg.)                                                                          Level     plants  tion                                           Animal  Wt.    day  day  2    7    2     rate                           Group No.     (kg.)  25   26   days days weeks %                              ______________________________________                                              1       13     22   21   basal                                                                              basal                                                                              none                                 1     2       19.5   21   23   "    "    "     100                                  3       13     20   22   "    "    "                                          4       16.5   19   --   basal                                                                              re-  present                                                                  cov-                                                                          ered                                      2     5       13     22   --   "    re-  "     0                                                                  cov-                                                                          ered                                            6       11.5   25   --   "    re-  "                                                                        cov-                                                                          ered                                            7       14.4   7     7   basal                                                                              basal                                                                              none                                 3     8       12.2   11    9   "    "    "     66                                   9       15.7   11   11   basal                                                                              near present                                                                  basal                                     ______________________________________                                    

A comparison of the incidence of abortion in Groups 1 to 3 shows thatthe duration of administration is an important feature of the treatmentand that administration of the medicament over 48 hours gives a betterabortion rate as compared to that obtained when treatment is given over24 hrs.

EXAMPLE 8

The bitches in Example 7 which failed to abort were treated withsustained release intravaginal devices containing fluprostenol sodium.The animals were treated on day 57 of pregnancy with annuli devicesdescribed in Example 7. These devices were designed to release 20 to 25μg./kg. of medicament over 24 hr. when inserted into the vagina of thepregnant bitches. The devices were removed after 24 hr. The results aresummarised in Table 6.

                  TABLE 6                                                         ______________________________________                                        Induction of parturition in pregnant bitches.                                              Drug       Day of                                                Animal                                                                              Wt.    Administered                                                                             Treat-                                                                              Day of Expected day                             (No.) (kg.)  (μg.)   ment  Whelping                                                                             of Whelping                              ______________________________________                                        4     19     493        57    58     62-64                                    5     16     384        "     58     "                                        9     20     342        "     60     "                                        6     12.5   242        "     59     "                                        ______________________________________                                    

In all cases parturition was induced, and all of the bitches gave birthto live healthy pups.

EXAMPLE 9

(a) Preparation of copolymer-medicament mixture

Copolymer (B, as described in Example 5, 3.6 g.), fluprostenol sodium(10 mg., i.e. 2 ml. of a 5 mg./ml. solution) in water, C¹⁴ labelledfluprostenol sodium (5 μl. of a 0.02 mg./ml. solution in water, specificactivity 133 μCi/mg.), and 200 μl. of buffer solution (pH 7: a solutionof 3.9 g. of potassium dihydrogen orthophosphate and 6.1 g. of disodiumhydrogen orthophosphate dihydrate in 100 ml. of distilled water), weredissolved in a mixture of absolute ethanol (18 ml.) and distilled water(3.6 ml.) at 70° C. The solution was cast as a film which was air driedat room temperature for 18 hr. and then finally in vacuo at 80°/8 hr.

(b) Evaluation of in vivo release

The copolymer-medicament mixture was compression moulded at 110° C. togive a slab (0.16 cm. thick), and discs (weighing ca. 0.145 g.) were cutfrom the slab. The use of these discs as sustained release intravaginaldevices was tested in non-pregnant bitches.

Animals were separated into 4 groups of two, and the devices were placedhigh in the vaginal vault of the animals. At 1, 2, 5 and 8 hrs. thedevice were removed and the residual radioactivity measured. Acomparison of this with the original values showed that the devicesreleased medicament continuously over 8 hr. The results are summarisedbelow:

    ______________________________________                                                         % Drug desorbed from                                         Time (hours)     device                                                       ______________________________________                                        1                23-28                                                        2                44-49                                                        5                58-64                                                        8                65-80                                                        ______________________________________                                    

The incorporation of buffer in the device maintained the pH of thevagina at 6-7 during the release period and ensured reproducibility ofthe release of the medicament.

EXAMPLE 10

These hydrophilic copolymers will also act as drug releasing carriersfor medicaments having very low water solubility This can bedemonstrated using progesterone.

(a) Preparation of copolymer-medicament mixture.

Progesterone (10 mg.), lCμCi of C¹⁴ labelled progesterone (60.7μCi/m.mol. in 530 μl. benzene), and the copolymer (Example 5, copolymerB; lg.) were dissolved in tetrahydrofuran (10 ml.). The solution was airdried for 18 hr. at room temperature and finally at 80° C. in vacuo for8 hr. The resulting copolymer-medicament mixture was moulded at 110° C.to give a film 0.02 cm. thick.

(b) In vitro release of medicament.

0.2 g. of the film was supported from the end of a stirrer into 500 ml.of distilled water at 37° C. The stirring rate was 150 r.p.m. Thedesorption of the medicament with time was estimated by measuring theradioactivity in the distilled water. After 24 hr. the swollen film wasdissolved in tetrahydrofuran and the residual radioactivity measured.The desorption of medicament with time is summarised below:

    ______________________________________                                        Time (hr.)      % Progesterone desorbed                                       ______________________________________                                        1               8                                                             2               13                                                            3               18                                                            9               24                                                            17              33                                                            24              34                                                            ______________________________________                                    

The desorption of the progesterone from the device was determined by thepolymeric carrier and also by the low solubility of progesterone indistilled water. If the distilled water was continuously changed tomaintain "sink conditions", then approximately complete release of theprogesterone was achieved.

EXAMPLE 11

This Example illustrates further the use of a hydrophilic copolymer as adrug releasing carrier for a medicament of low water solubility[tamoxifen citrate, i.e.1-(p-β-dimethylaminoethoxyphenyl)-1,2-trans-diphenylbut-1-ene citrate].

(a) Preparation of copolymer-medicament mixture.

C¹⁴ labelled tamoxifen citrate (10 mg.; specific activity 0.33 μCi/mg.)and copolymer (Example 5, copolymer B; 1 g.) were dissolved intetrahydrofuran (10 ml.). The solution was air dried at room temperaturefor 18 hr. and finally at 80° C. in vacuo for 8 hr. Thecopolymer-medicament mixture was moulded at 110° C. to give a film 0.02cm. thick.

(b) In vitro release of medicament

Using the procedure described in Example 10(b) but using the tamoxifencitrate-copolymer mixture the following results were obtained fordesorption of the medicament:

    ______________________________________                                        Time (hr)            % desorbed                                               ______________________________________                                        0.1                  6                                                        0.2                  16                                                       0.5                  23                                                       1                    34                                                       3                    39                                                       17                   42                                                       72                   50                                                       ______________________________________                                    

This illustrates that tamoxifen citrate, which is sparingly soluble inwater, can be released in a sustained fashion from the abovementioncopolymer.

What we claim is:
 1. The sustained release delivery means comprising:(a)a functionally effective amount of a biologically active agent; and (b)a hydrophilic linear block polyoxyalkylene-polyurethane copolymer of thetype ABABAB . . . having blocks A linked to blocks B, substantiallydevoid of cross-linking, wherein A represents a hydrophilic blockcomprising one or more polyoxyalkylene moieties of molecular weight 600to 6000, and B represents a hydrophobic block comprising a polyurethanemoiety obtainable by reacting an aromatic or aliphatic diisocyanate witha short chain oxyalkylated diphenol.
 2. A sustained release deliverymeans as claimed in claim 1 wherein B represents a hydrophobic blockcomprising a polyurethane moiety obtainable by reacting an aromatic oraliphatic dissocyanate with a short chain oxyalkylated diphenol and atleast one alkyleneglycol of not more than 6 carbon atoms.
 3. A sustainedrelease delivery means as claimed in claim 1 wherein A represents ahydrophilic block comprising polyoxyethylene of molecular weight 600 to6000.
 4. A sustained release delivery means as claimed in claim 1wherein the short chain oxyalkylated diphenol is1,1'-isopropylidene-bis-p-phenyleneoxy-dipropanol-2.
 5. A sustainedrelease delivery means as claimed in claim 1 which contains abiologically acceptable buffer.
 6. A sustained release delivery means asclaimed in claim 2 which contains a biologically acceptable buffer. 7.The sustained release delivery means comprising:(a) a functionallyeffective amount of a biologically active agent; and (b) a hydrophiliclinear block polyoxyalkylene--polyurethane copolymer substantiallydevoid of cross-linking and comprising the reaction product of (1) anaromatic or aliphatic diisocyanate, (2) at least one polyoxyalkylene ofmolecular weight 600 to 6000, and (3) a short chain oxyalkylateddiphenol.
 8. A sustained release delivery means as claimed in claim 7wherein said block copolymer (b) comprises the reaction product of (1)an aromatic or aliphatic diisocyanate, (2) at least one polyoxyalkyleneof molecular weight 600 to 6000, (3) a short chain oxyalkylateddiphenol, and (4) at least one alkyleneglycol of not more than 6 carbonatoms.
 9. A sustained release delivery means as claimed in claim 7 whichcontains a biologically acceptable buffer.
 10. A sustained releasedelivery means as claimed in claim 8 which contains a biologicallyacceptable buffer.